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DOI: 10.1055/a-2106-1678
Regiodivergent Synthesis of Brominated Pyridylthiophenes by Overriding the Inherent Substrate Bias
This work was supported by JSPS KAKENHI (JP19H02717) and Hyogo Science and Technology Association. This work was performed under the Cooperative Research Program of the Network Joint Research Center for Materials and Devices.
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Abstract
A regiocontrolled functionalization of a pyridylthiophene scaffold was accomplished. Regioselectivity for deprotonation of the pyridylthiophene was switched by changing the reaction conditions, including the metal amide base and the solvent. Subsequently, in situ transmetalation and halogen dance on the corresponding organometallic species were controlled by additives and the reaction temperature, as well as by the above reaction conditions. This method successfully enabled the synthesis of four iodinated constitutional isomers from a single starting material, 2-(5-bromo-2-thienyl)pyridine.
Key words
deprotonation - halogen dance - organometallic reagents - pyridylthiophenes - regioselectivitySupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/a-2106-1678.
- Supporting Information
Publikationsverlauf
Eingereicht: 14. Mai 2023
Angenommen nach Revision: 05. Juni 2023
Accepted Manuscript online:
05. Juni 2023
Artikel online veröffentlicht:
24. Juli 2023
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References and Notes
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- 23 2-(3-Bromo-5-iodo-2-thienyl)pyridine (4) A flame-dried 20 mL Schlenk tube equipped with a Teflon-coated magnetic stir bar and a rubber septum was charged under argon with 2-(5-bromo-2-thienyl)pyridine (1) (200.4 mg, 0.835 mmol, 1.0 equiv) and toluene (4.0 mL). The resulting solution was cooled to –78 °C, and changed into a slurry. A 2.0 M solution of LDA in THF/heptane/ethylbenzene (0.62 mL, 1.2 mmol, 1.5 equiv) was added to the Schlenk tube at –78 °C and the mixture was stirred at –78 °C for 90 min, whereupon the precipitate dissolved. I2 (422.8 mg, 1.666 mmol, 2.0 equiv) was added to the mixture in one portion (the septum was temporarily removed), and the resulting mixture was warmed to r.t. and stirred at r.t. for 30 min. The mixture was treated with Et2O (20 mL) and sat. aq Na2S2O3 (20 mL). After partitioning, the aqueous layer was extracted with Et2O (20 mL). Each of the organic layers was washed with H2O (20 mL), and the combined organic extracts were concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography [silica gel, hexane/Et2O (20:1)] to give a pale yellow solid; yield: 200.6 mg (0.548 mmol, 66%); Rf = 0.37 (hexane/Et2O = 9:1); mp 66.8–67.7 °C. IR (ATR): 1582, 1567, 1518, 1460, 1435, 1423, 1305, 1154, 994, 975, 821, 776, 738, 713, 659 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.57 (d, 1 H, J = 4.8 Hz), 8.25 (d, 1 H, J = 7.8 Hz), 7.76 (ddd, 1 H, J = 7.8, 7.8, 1.6 Hz), 7.23 (ddd, 1 H, J = 7.8, 4.8, 1.2 Hz), 7.20 (s, 1 H). 13C{1H} NMR (100 MHz, CDCl3): δ = 150.7, 149.7, 145.2, 141.3, 136.7, 123.0, 120.3, 107.3, 77.0. HRMS (EI+): m/z [M+] calcd for C9H5 79BrINS, 364.8365; found: 364.8373.
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- 25 2-(4-Bromo-5-iodo-2-thienyl)pyridine (5) A flame-dried 20 mL Schlenk tube equipped with a Teflon-coated magnetic stir bar and a rubber septum was charged under argon with 1 (100.3 mg, 0.418 mmol, 1.0 equiv), THF (1.6 mL), and DMPU (0.4 mL). The resulting solution was cooled to –78 °C. A 2.0 M solution of LDA in THF/heptane/ethylbenzene (0.62 mL, 1.2 mmol, 1.5 equiv) was added to the Schlenk tube at –78 °C and the mixture was stirred at –78 °C for 60 min. I2 (211.4 mg, 0.833 mmol, 2.0 equiv) was added in one portion (the septum was temporarily removed), and the resulting mixture was warmed to r.t. and stirred at r.t. for 30 min. The mixture was treated with Et2O (10 mL) and sat. aq Na2S2O3 (10 mL). After partitioning, the aqueous layer was extracted with Et2O (10 mL). Each of the organic layers was washed with water (10 mL), and the combined organic extracts were concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography [silica gel, hexane/Et2O (20:1)] to give a pale yellow solid; yield: 112.6 mg (0.308 mmol, 74%); Rf = 0.23 (hexane/Et2O = 9:1); mp 101.3–103.0 °C. IR (ATR): 1584, 1564, 1461, 1433, 1408, 1321, 1289, 994, 979, 813, 772 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.56–8.53 (m, 1 H), 7.71 (ddd, J = 7.8, 7.8, 1.2 Hz, 1 H), 7.57–7.53 (m, 1 H), 7.32 (s, 1 H), 7.19 (ddd, J = 7.8, 4.8, 1.2 Hz, 1 H). 13C{1H} NMR (100 MHz, CDCl3): δ = 150.80, 150.78, 149.8, 137.1, 126.7, 123.0, 120.9, 118.3, 80.3. 13C{1H} NMR (100 MHz, CD3CN): δ = 152.0, 151.2, 150.4, 138.3, 127.8, 124.2, 121.4, 119.3, 81.5. HRMS (EI+): m/z [M+] calcd for C9H5 79BrINS: 364.8365; found: 364.8374.
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- 28 2-(5-Bromo-3-iodo-2-thienyl)pyridine (2) A flame-dried 20 mL Schlenk tube equipped with a Teflon-coated magnetic stir bar and a rubber septum was charged under argon with 1 (100.0 mg, 0.416 mmol, 1.0 equiv) and THF (1.0 mL). A 1.0 M solution of TMPMgCl·LiCl in THF/toluene (0.83 mL, 0.83 mmol, 2.0 equiv) was added to the Schlenk tube at r.t., and the resulting mixture was stirred at r.t. for 150 min. I2 (211.9 mg, 0.835 mmol, 2.0 equiv) was added to the mixture in one portion (the septum was temporarily removed), and the resulting mixture was stirred at r.t. for 30 min. The mixture was then treated with Et2O (10 mL) and sat. aq Na2S2O3 (10 mL). After partitioning, the aqueous layer was extracted with Et2O (5 mL). Each of the organic layers was washed with H2O (5 mL), and the combined organic extracts were concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography [silica gel, hexane/Et2O (9:1)] to give a pale yellow solid; yield: 80.9 mg (0.221 mmol, 53%); Rf = 0.33 (hexane/Et2O = 9:1); mp 45.7–46.9 °C. IR (ATR): 1583, 1567, 1509, 1460, 1435, 1424, 994, 985, 819, 802, 775, 738, 661 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.60–8.57 (m, 1 H), 8.28–8.24 (m, 1 H), 7.77 (ddd, J = 7.6, 7.6, 1.6 Hz, 1 H), 7.25 (ddd, J = 7.6, 5.0, 0.8 Hz, 1 H), 7.13 (s, 1 H). 13C{1H} NMR (100 MHz, CDCl3): δ = 151.4, 149.7, 144.5, 139.8, 136.5, 123.1, 120.4, 116.6, 75.6. HRMS (EI+): m/z [M+] calcd for C9H5 79BrINS: 364.8365; found: 364.8370.
- 29 2-(5-Bromo-4-iodo-2-thienyl)pyridine (3) A flame-dried 20 mL Schlenk tube equipped with a Teflon-coated magnetic stir bar and a rubber septum was charged under argon with 1 (100.0 mg, 0.416 mmol, 1.0 equiv), ZnCl2·TMEDA (315.5 mg, 1.250 mmol, 3.0 equiv), THF (3.2 mL), and DMPU (0.8 mL). The resulting solution was cooled to –50 °C. A 2.0 M solution of LDA in THF/heptane/ethylbenzene (0.62 mL, 1.2 mmol, 3.0 equiv) was added to the Schlenk tube at –50 °C, and the mixture was stirred at –50 °C for 60 min. I2 (422.8 mg, 1.666 mmol, 4.0 equiv) was added to the mixture in one portion (the septum was temporarily removed), and the resulting mixture was warmed to r.t and stirred at r.t. for 30 min. The mixture was then treated with Et2O (20 mL) and sat. aq Na2S2O3 (20 mL). After partitioning, the aqueous layer was extracted with Et2O (10 mL), and each of the organic layers was washed with water (10 mL). The combined organic extracts were concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography [silica gel, hexane/Et2O (20:1)] to give a pale yellow solid; yield: 101.1 mg (0.276 mmol, 66%); Rf = 0.27 (hexane/Et2O = 9:1); mp 93.0–93.4 °C. IR (ATR): 1582, 1564, 1461, 1432, 1410, 1315, 1288, 1158, 995, 771 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.53 (d, J = 4.8 Hz, 1 H), 7.69 (ddd, J = 7.6, 7.6, 1.6 Hz, 1 H), 7.54 (d, J = 7.6 Hz, 1 H), 7.37 (s, 1 H), 7.18 (ddd, J = 7.6, 4.8, 1.2 Hz, 1 H). 13C{1H} NMR (100 MHz, CDCl3): δ = 150.7, 149.8, 147.6, 137.0, 131.6, 122.9, 119.6, 118.3, 86.4. HRMS (EI+): m/z [M+] calcd for C9H5 79BrINS: 364.8365; found: 364.8374.
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